The present invention relates to a pharmaceutical composition containing a fatty acid and a water-soluble silicate polymer in a pharmaceutically effective amount for use as a medicine such as an anti-allergic agent. The present invention relates to a method of enhancing the activity of a water-soluble silicate polymer in a pharmaceutical composition by mixing a saturated fatty acid and a water-soluble silicate polymer.
Every cell, which is the fundamental unit of the living body, is surrounded by membrane. The membrane is not only useful as a protective envelope so that the activity inside the cell can be normally carried out but also plays a role as a door for taking the nutrients therein and for excreting the waste products and also as a transmitter of information into and from the cell. In the cells of higher animals, organelles of an internal membrane system are present inside in addition to the surrounding cell membrane. Organelles have variously differentiated roles. For example, mitochondria have a function of energy production, catabolic metabolism, cell respiration, etc.; the lysosome carries out digestion of substances inside and outside the cells since it contains many hydrolases therein; the endoplasmic reticulum is a place where biosubstances such as protein and lipid are produced; and the Golgi apparatus carries out transport and secretion of the biosubstances synthesized in endoplasmic reticulum to the outside of the cells.
The main components of each of the plasma membrane of the cells and of the organelle membrane are polar lipids and membrane proteins. Most of the lipids contained in the biomembrane are phospholipids in which phosphatidylcholine (PC) and phosphatidylethanolamine (PE) occupy 60-90% thereof. When the fatty acid composition of the phospholipid in hepatic cells of rat was investigated, palmitic acid was 37% and stearic acid was 32% in the PC of the plasma membrane while, in PE, palmitic acid was 26% and stearic acid was 33%. In the PC and PE of mitochondria, the amount of palmitic acid was 27% in both phospholipids and that of stearic acid was 22% and 27%, respectively. As such, saturated fatty acids such as palmitic acid and stearic acid have been known as important constituent components for the biomembrane.
Silicon is a natural element which is widespread in organisms of the animal and plant kingdoms. In particular, it exists as silicate in animal tissues like hair, feather, bone and skin and is known as an essential element in osteogenesis. In animal tissues, it is involved in cross linkage of collagen tissues and comprises one of the components of acidic mucopolysaccharides. Silicon is thus an essential element for a living body. However, few pharmacological activities of the administration to animals are presently known, for example, immuno-suppressing activity through its anti-macrophage effect and antidiabetic activity. As a medicine, some silicates like magnesium silicate and aluminum silicate are just used as antacids.
The present inventor has previously carried out continued studies taking note of the functions and the pharmacological actions of silicic acid and silicon-containing compounds in vivo. With regard to silicate polymers, a water-soluble silicate polymer manufactured by polymerization of water-soluble silicic acids by a method originated by the present inventor has been found to have excellent actions whereby any abnormality of the nervous system, endocrine system and immune system caused by cellular dysfunction of the living body occurring in a diseased state is adjusted and repaired whereby biofunction can be normalized.
The above pharmacological activities are not available in the state of a monomer but they have been found to be exhibited by water-soluble silicate polymers. For example, a water-soluble silicic acid polymer and a method for manufacturing the polymer are disclosed in Japanese Patent 2,698,908 and its medical uses as an analgesic agent, anti-allergic agent, paresthesia improving agent, peripheral blood flow improving agent and anti-inflammatory agent are mentioned in Japanese Patents 2,588,109, 2,727,441, 2,727,442, 2,948,784 and 3,113,619, respectively, and corresponding U.S. Pat. Nos. 5,534,509, 5,658,896, and 5,807,951 each to Konishi et al. However, it is desirable to improve the pharmacological activity of the said silicate polymer.
The present inventor has further carried out a study for the above-mentioned water-soluble silicate polymer and, as a result, has found that an increased pharmacological activity of the said silicate polymer can be obtained from a combination of the water-soluble silicate polymer with a saturated fatty acid which is a main constituting component of the cell membrane whereupon the present invention has been achieved.
The present invention relates to a pharmaceutical composition which is useful as a medicine such as an anti-allergic agent or an anti-inflammatory agent, wherein a water-soluble silicate polymer and a saturated fatty acid are contained in a pharmaceutically effective amount. The present invention also provides a method for enhancing the activity of a water-soluble silicate polymer by adding a saturated fatty acid to a product containing the water-soluble silicate polymer. The water-soluble silicate polymers employed in the invention may have a molecular weight distribution in the range of about 4,800 to about 2,000,000, preferably about 13,000 to about 1,000,000, which distribution is unimodal and which is determined by gel-filtration, ultrafiltration, electrophoresis and the like. The degree of polymerization of the said silicate polymers may be in the range of about 75 to about 33,000, preferably about 210 to about 16,500, wherein the monomer unit is xe2x80x94(SiO2)xe2x80x94.
The saturated fatty acid contained as an effective ingredient in the pharmaceutical compositions of the present invention is a general name for a fatty acid having neither a double bond nor a triple bond in a molecule and is represented by the chemical formula CnH2n+1COOH. Preferably, it is a straight chain or branched chain saturated fatty acid having about 8 carbon atoms to about 26 carbon atoms. Such a fatty acid may be used solely or as a mixture of plural fatty acids. The acid may be used either in a free form or as a salt such as a sodium salt and potassium salt and it is preferred to use it in a water-soluble form.
For the purpose of making a pharmaceutical composition of the invention, an aqueous solution containing one or more water-soluble silicate polymers is preferably dried to a powder. The pharmaceutical compositions of the present invention may be formed by a method of adding a solution of the saturated fatty acid to the water soluble silicate polymer to form a solution. By this method, the pharmacological activity of a water soluble silicate polymer or polymers is greatly increased with respect to treatment of allergies and inflammation. The saturated fatty acid and water-soluble silicate polymer, effective ingredients of the present invention, can be formulated for various pharmaceutical compositions by combining with a suitable carrier or diluent for medical use.
The substance of the present invention comprises water soluble silicate polymers mixed with saturated fatty acids. The water soluble silicate polymers may be obtained by polymerization and/or by extraction from plants, animals or fungi. The water-soluble silicate polymer, one of the effective ingredients of the pharmaceutical composition of the present invention, may be produced by polymerization of silicic acids or silicates including orthosilicic acid, metasilicic acid, mesodisilicic acid, mesotrisilicic acid, mesotetrasilicic acid, etc. The silicates which may be used to produce the water-soluble silicate polymers of the present invention are the salts of silicic acids, for example, salts of silicic acids with alkali metals such as sodium and potassium. Materials containing silicic acid, for instance, water glass which is a concentrated aqueous solution of alkali salts of silicic acid, may also be used. Further, a silicate solution prepared by heating and dissolving silicon oxide in alkaline aqueous solution may be utilized. Examples of water-soluble sodium silicates which may be used to produce the silicate polymers of the present invention are sodium metasilicate anhydrous, sodium metasilicate pentahydrate, sodium sesquisilicate, sodium orthosilicate, and mixtures thereof.
The water-soluble silicate polymers of the invention may have a molecular weight distribution in the range of about 4,800 to about 2,000,000, preferably, about 13,000 to about 1,000,000, which distribution is unimodal and which is determined by gel-filtration, ultrafiltration, electrophoresis and the like. The degree of polymerization of the said silicate polymers is indicated in the range of about 75 to about 33,000, preferably about 210 to about 16,500, wherein the monomer unit is xe2x80x94(SiO2)xe2x80x94.
In embodiments for producing the silicate polymers of the present invention, a water-soluble silicate such as sodium orthosilicate, sodium metasilicate, potassium orthosilicate or potassium metasilicate, or a silicic acid containing material such as water glass is dissolved in an aqueous solution. Since said aqueous solution of the silicates has a high pH value, it is preferable to adjust the solution to pH 2-10, more preferably, pH 4-9.5, by the use of a conventional acid such as hydrochloric acid, sulfuric acid or acetic acid. It is desirable to add a saccharide carrier or diluent such as lactose, mannitol, sorbitol, sucrose, glucose, fructose, galactose, or mixtures thereof to the aqueous solution. A salt such as sodium chloride, potassium chloride or sodium sulfate may also be added to the solution.
Pharmaceutically effective water-soluble silicate polymers, methods for making and using them to treat diseases and medical conditions are disclosed in Japanese Patents 2,698,908 2,588,109, 2,727,441, 2,727,442, 2,948,784 and 3,113,619, and corresponding U.S. Pat. Nos. 5,534,509, 5,658,896, and 5,807,951 each to Konishi et al, the disclosures of which are each herein incorporated by reference in their entireties.
A crude drug extract obtained from animal, fungus or plant materials such as tanjin (Salvia militiorrhiza radix), shireisi (Ganoderma lucidum) and scouring rush (Equisetum hiemale) or an extract from inflammatory tissue inoculated with vaccinia virus contains the above water-soluble silicate polymers. Therefore, water-soluble silicate polymers purified or extracted from the extracts may be utilized as an ingredient of the composition of the present invention. The activity of the water-soluble silicate polymers contained in the extract may also be enhanced by addition of the saturated fatty acid to the crude drug or the extract.
Crude drug extracts which may be employed as a source of the water-soluble silicate polymers for use in the present invention are disclosed in copending U.S. application Ser. No. 09/200,918, for xe2x80x9cCRUDE DRUG EXTRACTS, AND METHODS FOR MAKING AND STANDARDIZING SAME,xe2x80x9dfiled Nov. 30, 1998 in the name of Jin-emon Konishi, the disclosure of which is incorporated by reference in its entirety. As disclosed therein, the crude drug extracts contain not less than 0.05 mg of soluble silicon compounds calculated as silicon per gram of the dry crude drug. The crude drug extract may be obtained by extraction of various crude drugs, for example, animal and plant crude drugs including tanjin (Salviae militiorrhizae radix), shireishi (Ganoderma lucidum), creeping saxifrage (Saxifraga stolonifera), scouring rush (Equisetum hiemale), Chinese gutta percha, plantago herb, plantago seeds, chorei (polyporus sclerotium), saiko (bupleurum root), Japanese angelica root, elderberry, bukuryo (poria sclerotium), pueraria root, crude aloe, ginseng, ginger, alisma rhizome, schisandra fruit, sanshiti (root of Panax nothoginseng), jujube, chinpi (citrus unshiu peel), bakumondo (ophiopogon tuber), young staghorn, oriental bezoar, lumbicusa, bear bile, longgu, etc. The crude drug extracts may be obtained by extraction with water, ethanol or a suitable extracting solvent to which an additive such as phenol is added. At that time, extraction and concentration of the active substances may be enhanced by heating or changing the pH of the solvent. Thus, the following manufacturing methods may be exemplified for obtaining crude drug extracts as a source of water-soluble silicate polymers for use in accordance with the present invention:
1) Pure water is added to a crude drug material, the mixture is boiled with stirring and the insoluble matters are removed by filtration or the like to give an extract solution. The extract solution is concentrated if necessary and spray-dried or freeze-dried in vacuo to give a powder.
2) Pure water is added to a crude drug material, the mixture is boiled with stirring and the insoluble matters are removed by filtration or the like to obtain an extract. Pure water is further added to the residue, pH is adjusted to an alkaline region (to 8.5-10.5, for example to around 9.5), then the mixture is boiled with stirring again, and the insoluble matters are removed by filtration or the like to obtain an extract, and the extract is adjusted to about the neutral pH region and combined with the already-prepared first extract. Then, the combined extract is concentrated and/or evaporated to dryness if necessary to give a powder. Spray-drying or freeze-drying in vacuo to give a powder may be employed as in the above-mentioned method 1).
3) To a crude drug material is added a 1% aqueous phenol solution followed by boiling with stirring and the insoluble matters are removed by filtration or the like to give an extract solution. The extract solution is concentrated if necessary and spray-dried or freeze-dried in vacuo to give a powder.
4) Pure water and ethanol are added to a crude drug material, the mixture is boiled with stirring and the insoluble matters are removed by filtration or the like to give an extract solution. The extract solution is concentrated if necessary and spray-dried or freeze-dried in vacuo to give a powder.
5) After conducting the extracting operations as described in the above methods 1) to 4), the pH of the extract is adjusted to weakly alkaline (for example, to pH of around 8.5) followed by concentrating, and the pH of the concentrate is adjusted to nearly the neutral region followed by pulverizing in the same manner as mentioned above.
Conventional pH adjusting agents, such as inorganic or organic bases and acids and salts may be employed to obtain a desired pH for the extracting solvent and extract. For example, alkali metal hydroxides such as sodium hydroxide, and potassium hydroxide, etc. may be employed to obtain a desired alkaline pH. Exemplary acids which may be employed to adjust pH to the neutral range include hydrochloric acid, sulfuric acid, and hydrobromic acid, etc.
The crude drug extracts are characterized and evaluated for pharmaceutical effectiveness by specifying the soluble silicon compound content of the crude drug extract. The content of the soluble silicon compounds in the dried crude drug extract obtained by the above-mentioned manufacturing methods can be analyzed by the following method and is able to be regulated as an amount calculated as silicon.
Thus, the crude drug extract is added to water (to an extent of 1 mg/ml), the mixture is subjected to stirring and an ultrasonic treatment. In preferred embodiments, the stirring is conducted at room temperature for about ten minutes and ultrasonic treatment is conducted at room temperature for about ten minutes. Then, the insoluble matters are removed by filtration or centrifugation, and the amount of silicon in the resulting solution is measured by a molybdenum blue method. In addition, an inhibiting action of the same sample solution against the production of plasma kallikrein is measured and is confirmed as an index for the soluble silicon compounds. The measured inhibiting action against plasma kallikrein production may be employed as an index for the measurement and confirmation of the titer (potency of the biological activity) of the soluble silicon compounds having a biological activity.
In embodiments of the invention, extracts from an activated tissue which may be employed as a source of the water-soluble silicate polymers for use in the compositions and methods of the present invention may be extracts from inflammatory tissue inoculated with vaccinia virus disclosed in Japanese Examined Patent Publications Sho-63/039,572 B, Sho-63/025,600 B and Hei-03/043,279 B, Japanese Patent No. 2,594,222 and U.S. Pat. No. 5,013,558 to Konishi, U.S. Pat. No. 5,560,935 to Konishi, et al, and U.S. Pat. No. 6,051,613 to Ohno et al. The disclosures of Japanese Examined Patent Publications Sho-63/039,572 B, Sho-63/025,600 B and Hei-03/043,279 B, Japanese Patent No. 2,594,222, and U.S. Pat. Nos. 5,013,558 to Konishi, 5,560,935 to Konishi, et al. and 6,051,613 to Ohno et al are herein incorporated by reference in their entireties. A method for producing an extract from inflammatory tissue inoculated with vaccinia virus for use in the present invention is described, for example, in Example 1 of Japanese Examined Patent Publication Sho-63/039,572 B and Japanese Patent No. 2,594,222. Methods for producing extracts from inflammatory tissue inoculated with vaccinia virus for use in the present invention are also described, for example, in U.S. Pat. No. 5,013,558 to Konishi at column 1 line 44 to column 3 line 22, and in Examples 1 and 2 at column 3 lines 33 to 62, U.S. Pat. No. 5,560,935 to Konishi, et al. at column 2 line 55 to column 3 line 14, and column 3 line 33 to column 4 line 64, and in Examples 1 and 2 at column 5 line 6 to column 6 line 8, and U.S. Pat. No. 6,051,613 to Ohno at column 3 line 61 to column 6 line 24, and column 8 lines 6-29, which are herein incorporated by reference in their entireties.
A commercially available drug preparation of an extract from inflammatory rabbit skin inoculated with vaccinia virus is sold in Japan under the trade name Neurotropin by Nippon Zoki Pharmaceutical Co., Osaka, Japan. As mentioned at pages 1,927 and 1,928 of xe2x80x9cDrugs in Japan, Ethical Drugsxe2x80x9d (22nd edition, 1998-1999; edited by Japan Pharmaceutical Information Center; published by Yakugyo Jiho Co., Ltd.), this preparation is a drug containing non-proteinaceous active substances extracted and isolated from inflammatory rabbit skin inoculated with vaccinia virus. The preparation has been used for treatment of lower back pain, neck-shoulder-arm syndrome, periarthritis scapulohumeralis, arthrosis deformans, symptomatic neuralgia, post-herpetic neuralgia, pruritis due to dermatological diseases (such as eczema, dermatitis and urticaria), allergic rhinitis, and sequelae of subacute myelo-optico-neuropathy (such as coldness, pain and paresthesia/dysesthesia). It is available as an ethical drug in the form of injections (subcutaneous, intramuscular and intravenous) and tablets.
Neurotropin was used in an experimental study at the School of Medicine, University of California, Davis, to evaluate its influence on thymic microenvironmental abnormalities of New England black mice as reported by Y. Takeoka et al, Int. J Immunotherapy, XI(2), pp. 49-56 (1995). As taught by Takeoka et al, Neurotropin is a non-protein extract isolated from the inflamed dermis of rabbits inoculated with vaccinia virus and it has been reported in the literature as: 1) having beneficial effects on immune-depressed animals, 2) clinically useful as an analgesic and as an anti-allergy drug with few side-effects in humans, 3) improving the immune status of murine lupus in (NZB/NZW) F1 mice, and 4) inhibiting the development of EAE in Lewis rats, an autoimmune model of human multiple sclerosis.
The commercially available extract, Neurotropin, may be employed as a source for the water-soluble silicate polymer used in the compositions and methods of the present invention. The descriptions, properties and dosages of Neurotropin reported in the above-mentioned xe2x80x9cDrugs in Japan, Ethical Drugsxe2x80x9d and the Takeoka et al article are incorporated herein by reference in their entireties.
The physiologically active substance, i.e., an extract from inflamed skins inoculated with vaccinia virus, prepared as described in U.S. Pat. No. 5,560,935 may exhibit the following properties:
(1) Characteristic: an amorphous and hygroscopic powder with pale yellowish brown color containing 1-20 micrograms/mg (e.g. 2-10 micrograms/mg) of silicon components which are calculated as silicon;
(2) Solubility: it is soluble in water, methanol and ethanol and is insoluble in benzene and ether;
(3) pH: 6.0-8.3;
(4) Ultraviolet absorptions: max=265-275 nm;
(5) Color reactions: amino acid (positive to a ninhydrin reaction), saccharide (positive to an orcinol-iron(III) chloride-hydrochloric acid method), phosphorus (positive to a molybdenum blue method), protein (negative to a trichloroacetic acid method) and phenol (negative to a ferric chloride method).
The physiologically active substance, i.e., an extract from inflamed skins inoculated with vaccinia virus, prepared as described in U.S. Pat. No. 6,051,613 may exhibit the following properties:
(1) Appearance: Pale yellowish brown and hygroscopic powder.
(2) Solubility: Soluble in water, methanol and ethanol.
(3) Ultraviolet adsorption: xcexmax=255-275 nm.
(4) Ninhydrine reaction: Positive.
(5) One ml of perchloric acid is added to 2 mg of the extract of the present invention, and is heated until the solution become colorless. 3 ml of dilute hydrochloric acid, 0.4 g of amidol hydrochloride and 8 g of sodium hydrogen sulfite are dissolved in 100 ml of water, and then 2 ml of the resulting aqueous solution, 1 g of ammonium molybdate and 30 ml of water are mixed. 2 ml of the mixture is added to the above solution containing the extract of the present invention. Finally, the solution shows a blue color.
(6) 5 mg of the extract of the present invention is dissolved in 10 ml of water, 0.2 g of orcine and 0.135 g of iron(II)ammonium sulfate are dissolved in 5 ml of ethanol, 83 ml of hydrochloric acid is added to the mixture, and water is added until the total becomes 100 ml. 3 ml of the resulting mixture is added to 1 ml of the above solution containing the extract of the invention and heated in a boiling water bath. Finally, the solution shows a green color.
(7) Silver nitrate reagent is added to an aqueous solution of the extract of the present invention and a precipitate is produced.
(8) Contains nucleic acid bases.
(9) Various methods of protein detection are negative.
The inflamed or infected tissues may be animal tissues, organs or cultured cells inoculated or infected with vaccinia virus, a poxvirus.
In embodiments of the invention, a mixture of: a) one or more water-soluble silicate polymers obtained by polymerization, and b) one or more water-soluble silicate polymers obtained from an extract, such as an extract from inflammatory tissue inoculated with vaccinia virus, or a crude drug extract from a plant, animal or fungus, may be employed. For example, a bioactivating substance comprising a mixture of a water-soluble silicate polymer obtained by polymerization, and an extract from activated tissue may be employed, which bioactivating substance is disclosed in copending U.S. application Ser. No. 09/551,135, filed Apr. 17, 2000 in the name of Jin-emon Konishi for xe2x80x9c:NOVEL BIOACTIVATING SUBSTANCE,xe2x80x9d the disclosure of which is herein incorporated by reference in its entirety. As disclosed therein, the bioactivating substance may comprise at least one silicon component and exhibits positive color reactions to amino acid (by a ninhydrin reaction), saccharide (by an orcinol-iron (III) chloride-hydrochloric acid method), phosphorus (by a molybdenum blue method) and silicic acid (by a molybdenum blue method), and negative qualitative reactions to protein (by a trichloroacetic acid method) and phenol (by a ferric chloride method), said bioactivating substance having a silicon component content which is more than 20 xcexcg calculated as silicon per mg of dried substance.
For the purpose of manufacturing a pharmaceutical composition of the invention, an aqueous solution containing water-soluble silicate polymers is preferably dried to a powder. The powderization may be carried out according to a conventional method such as heating or lyophilization. To obtain a preferred powder, for example, the solution is dried by heating at 150xc2x0 C. to 250xc2x0 C. Also, a conventional lyophilization under reduced pressure may be used to powderize the solution. Powders of the water soluble silicate polymer in accordance with the present invention are storage stable for more than one year.
Compositions according to the present invention may comprise more than one water-soluble silicate polymer in the form of a mixture thereof.
To detect the production of silicate polymers, for example, a molybdenum blue coloration is measured. In this technique, a solution of ammonium molybdate is added to the aqueous solution of silicate, then sulfite solution is added to produce a blue coloration. The blue coloration is reduced as the polymerization of silicate proceeds. Also, the silicate polymers so produced can be separated by gel-filtration under acidic conditions at high molecular bands. An aliquot of this separated fraction is decomposed under alkali conditions to detect silicates by the molybdenum blue reaction.
The saturated fatty acid contained as an effective ingredient in the pharmaceutical composition of the present invention is a general name for a fatty acid having neither a double bond nor a triple bond in a molecule and is represented by the chemical formula CnH2n+1COOH. Preferably, it is a straight chain or branched chain saturated fatty acid having about 8 carbon atoms to about 26 carbon atoms. Exemplary of straight saturated fatty acids which may be employed are caprylic acid (8:0), capric acid (10:0), lauric acid (12:0), myristic acid (14:0), pentadecanoic acid (15:0), palmitic acid (16:0), heptadecanoic acid (17:0), stearic acid (18:0), icosanoic acid (20:0), heneicosanoic acid (21:0), docosanoic acid (22:0), tricosanoic acid (23:0), lignoceric acid (24:0) or cerotic acid (26:0). Exemplary of branched saturated fatty acids which may be employed are 2-hexyldecanoic acid, 13-methylpentadecanoic acid or 16-methylheptadecanoic acid.
Such a fatty acid may be used solely or as a mixture of plural fatty acids. The acid may be used either in a free form, or as a salt, such as a sodium salt and a potassium salt. Also, it is preferred to use the fatty acid in a water-soluble form. With regard to the saturated fatty acid and salt thereof, those which are commercially available may be used or those which are extracted and purified from animal fat or vegetable oil may be used. In embodiments of the present invention, the saturated fatty acid may be employed in the form of an aqueous solution of a fatty acid salt or an aqueous dispersion of a free fatty acid. In the present invention, the saturated fatty acid can be used in a weight ratio of from about 1:20 to about 50:1 times the total amount of the silicate polymers, calculated as silicon, preferably about 1:10 to about 30:1 times the total amount of silicate polymers, calculated as silicon.
The saturated fatty acid and water-soluble silicate polymer, effective ingredients of the present invention, can be formulated for various pharmaceutical compositions by combining with a suitable carrier or diluent for medical use. The pharmaceutical composition may be prepared by a conventional method as a form for parenteral administration such as subcutaneous, intravenous, intramuscular, rectal or nasal administration or a form for oral administration, for example, tablets, capsules, powders or liquids. In manufacturing such preparations, mixtures of each of the effective components may be used, e.g. a mixture of extracts containing water-soluble silicate polymers. Also, in manufacturing such preparations, the effective components may be combined with other suitable pharmaceutically active components. In the pharmaceutical compositions or formulations, the admixture of water-soluble silicate polymer and fatty acid components of the present invention may be used solely or together in pharmaceutically effective amounts with pharmaceutically effective amounts of other pharmaceutically active components for treating animals or humans.
In the case of injections, the both effective components may be made into a solution, suspension or emulsion in aqueous solvents such as distilled water for injection, physiological saline solution or glucose solution, or in nonaqueous solvents such as propylene glycol. If necessary, a conventional additive such as a solubilizing agent, isotonic agent, suspending agent, emulsifying agent, stabilizing agent or preservative may be added. The powders in a vial with aseptic treatment may be dissolved in said solution such as distilled water for injection, physiological saline solution or Ringer""s solution just before using. Further, depending upon the state of the patient or the type of the disease, the components may be made into other preparation forms such as syrups, suppositories, inhalations, aerosols, eye drops or external preparations (ointments, gels or cataplasms) which are most suitable for the therapy.
In the case of preparations for oral use, the both components of the present invention may be made into tablets, diluted powders, granules or capsules with or without one or more suitable additives, for example, conventional fillers such as lactose, mannitol, corn starch, potato starch and calcium citrate, binders such as crystalline cellulose, cellulose derivatives (e.g. hydroxypropylcellulose), gum arabic, corn starch and gelatin, lubricants such as talc, extenders, moistening agents, buffering agents, stabilizing agents, preservatives, perfumes and the like.
In other embodiments, the polymeric silicate substances of the present invention may be mixed with at least one base material. The base material may be an oleaginous composition or fat/oil type material (e.g. cacao butter), an emulsifying base material, a water-soluble base material (e.g. Macrogol) or a hydrophilic base material, etc., to obtain a suppository.
A desired dose or a xe2x80x9cpharmaceutically effective amountxe2x80x9d of the effective components of the present invention may vary depending upon the patient to be treated (age, body weight or symptoms), preparation form, method of administration, period for administration, etc. In general 1 xcexcg/kg to 10 mg/kg per day (calculated as silicate) may be given to an adult for achieving the desired pharmaceutical effect. In the case of parenteral administration such as injections, the desired dose may be ⅓ to {fraction (1/10)} as large as an oral dose in general because of the difference in absorption rate. In the present invention, the saturated fatty acid can be used in a weight ratio of from about 1:20 to about 50:1 times the amount of the silicate polymers, calculated as silicon, preferably about 1:10 to about 30:1 times the amount of silicate polymers, calculated as silicon.
In a method of using the compositions of the present invention, the compositions are administered to a patient who has been diagnosed as having allergies and/or inflammation related to histamine release. Such patients are said to be xe2x80x9cknown to be in need of treatmentxe2x80x9d of a certain disease or condition involving histamine release, allergy or inflammation.